Ethan Russo The Entourage Effect

By David Heldreth

Ethan Russo, MD

If you’ve seen a terpene profile or heard the term “entourage effect” you probably have Ethan Russo, MD, to thank. Russo has served as the President of the International Cannabinoid Research Society and Senior Medical Advisor for GW Pharmaceuticals, an industry giant; and has participated in much of the research and writing on the topic of terpenes and cannabinoid interactions in circulation. He’s even working with the father of modern cannabis research Raphael Mechoulam at the new biotech company Phytecs. Cannabiz Journal was lucky enough to have some questions answered about Russo’s history and the future of cannabis.

CannaBiz Journal: I believe you started your path toward the endocannabinoid system while working with neuropathic pain patients. Would you care to expand on how that brought you to your current work with cannabis?

Ethan Russo: I had an interest in medicinal plants from my teen years, influenced by Euell Gibbons, but I had the traditional training in modern pharmacology in medical school. After residencies in pediatrics and neurology, and seven years in practice, I realized that I was giving increasingly toxic drugs to many of my chronic pain, migraine and epileptic patients with less and less benefit. There had to be a better way, and I rekindled my investigation of herbal alternatives. This accelerated after a three-month sabbatical in the Peruvian Amazon with the Machiguenga tribe in 1995. When I returned, I rapidly became embroiled in the cannabis controversy and began incorporating it and other medicinal plants into my practice. Inherent in all that was an appreciation of the endocannabinoid system and how it regulates almost every aspect of human physiology.

CBJ: How do you feel about cannabis naming classifications such as Indica/Sativa vs. terpene profiles and cannabinoid ratios?

ER: The way these names are employed in modern parlance is simply nonsense. What the patient needs to know is the cannabinoid and terpenoid profile of their medicine and how it will affect their illness. Dispensaries need to provide accurate, reliable and consistent cannabis assays to provide this information to consumers. Link to information: http://online.liebertpub.com/doi/pdf/10.1089/can.2015.29003.ebr.

CBJ: What are some of the most unique/rare cannabinoids/terpenes in cannabis? Are any found only in cannabis?

ER: Actually, all the terpenoids in cannabis are found in other plants. The critical key is how they synergize with cannabinoids, and in this regard, myrcene, limonene, pinene, caryophyllene, linalool, and terpinolene are likely the most significant. As to rarity, I might cite guaiol as special—a marker for Afghani genetics, and likely providing a mystical element to the cannabis experience.

CBJ: What cannabinoids/terpenes information do you believe is most important for states to focus on for labeling for recreational and medical cannabis?

ER: Right now, there is a super-abundance of myrcene in commercial chemovars. That’s fine if the person needs to sleep, but couch-lock is not conducive to a patient being able to work and study while medicating. We need to see more selective breeding and labelling for pinene, limonene, caryophyllene and linalool to emphasize their important medical contributions.

CBJ: Can terpenes from food have an effect on the way cannabinoids and cannabis affect the human body?

ER: Yes, but I doubt that eating a mango is going to make people a lot higher. While it is important to include a full terpenoid titer in edibles, they are probably most effective in inhalation, as with vaporization.”

CBJ: Currently there is a debate in the recreational and medical cannabis communities about the efficacy and safety of adding terpenes into cannabis extracts, more specifically regarding whether only cannabis-derived terpenes should be used, or if say a purified pinene, linalool or myrcene extract from another plant is appropriate to use in cannabis extracts and vaporizers. What is your perspective?

ER: I am strongly against commercial spiking of cannabis with terpenoids from external sources, as these are most often synthetically derived, have unspecified impurities with possible significant toxicity and were not designed for human ingestion, let alone inhalation. Rather, I believe that selective breeding for desired cannabinoid and terpenoid profiles is the proper path. The cannabis genome is so plastic that this can be achieved with concerted time and effort employing solely standard Mendelian techniques with no need for genetic modification, CRISPR technology for gene silencing or the like.

CBJ: Helichrysum species from South Africa have been found to contain CBG, echinacea has phytochemicals that work on the endocannabinoid system. What do you think the future of endocannabinoid plant medicine holds?

ER: These are but two examples of plants in nature that directly or indirectly affect the endocannabinoid system. I would add that probiotics and the prebiotic plants that serve as feedstock for the beneficial microbiome in the gut are extremely promising avenues for research toward better human health.

CBJ: What is Phytecs working on? Drug development? From phytochemicals?

ER: It is a varied program. Professor Mechoulam has developed semi-synthetic cannabidiol analogues that are currently in early-stage testing. We have an ambitious program to study the endocannabinoid system activity of a wide variety of medicinal plants, but have not ignored selective breeding of novel cannabis chemovars. We also have a strong dermatology research program directed by Dr. Tamas Biro in Hungary, and an active basic research agenda.

CBJ: What do you think of current drug developments from Insys Therapeutics (Synthetic CBD and liquid THC), Zynerba (THC/CBD prodrug gels) and GW Pharmaceuticals? Which holds most promise? Is it an apples to oranges comparison?

ER: I expect the natural cannabidiol extract, Epidiolex, from GW Pharmaceuticals to be approved by the FDA for Dravet and Lennox-Gastaut syndromes later this year. As for the rest, it remains to be seen whether they can prove safety and efficacy, and establish niches that are commercially viable. My bias is that single molecule new chemical entities (NCEs) are so 20th century! The pharmaceutical industry ignores the power of the entourage at its own peril.

CBJ: What terpene profiles do GW Pharmaceuticals Sativex and other products contain? Most of the information seems to be about the cannabinoid ratios, but are they also including terpene profiles from the cannabis in their products?

ER: That’s a trade secret. I won’t tell. Suffice it to say, GW Pharmaceutical’s current product line-up are whole plant extracts that do contain cannabinoids and terpenoids.

CBJ: Would you like to see pharmaceutical companies include terpenes in their cannabis products?

ER: That presupposes that they are cognizant of the possibility, and thus assumes facts not in evidence.

CBJ: What illnesses do you think cannabis holds the most promise for? Are there any coming treatments that people may be surprised by, such as THCv possibly providing a cannabis-based obesity treatment?

ER: Cannabis is well established in treatment of pain, especially neuropathic, various symptoms of multiple sclerosis, especially, spasticity, treating epilepsy, sleep disturbance, nausea and vomiting. Great promise is demonstrated for treatment of metabolic syndrome, diabetes, rheumatoid arthritis, inflammatory bowel diseases and other autoimmune disorders. Eventually, the scientific community will realize the tremendous potential of cannabis-based medicines in psychiatry for psychosis, depression, anxiety, PTSD and addiction—all areas in which current pharmacotherapy is woefully inadequate.

CBJ: What do you think is the most exciting thing in phytochemical/cannabis research currently?

ER: That’s just it; there is not one thing. If I had to choose, it would be the opioid-sparing effect of cannabis. Even the National Institutes of Health (NIH) is beginning to realize that opioids are far more dangerous than cannabis, and that it can be part of the solution. The legal and political barriers to cannabis research must fall.

CBJ: What is something about you or your research that you believe would surprise people? I’ve heard you mention the dichotomy of your “establishment ties” to your desire to be wearing a hemp outfit as an example.

ER: Sure, when I’m home, I choose to eat organic fruit and berries from the garden and sport hemp garb. In contrast, when I lecture, a business suit is the order of the day, because the seriousness of cannabis as medicine deserves that level of respect, but this isn’t about me. The most important thing for people to understand is that cannabis has been part of human medicine for thousands of years, that it is incredibly safe when properly utilized and that prohibition is nothing but a historical and medically unjustifiable aberration.

CBJ: Many people advocate that cannabis doesn’t interact with other medications. Have you seen much of the research on CBD acting on the CYP450 enzymes in the liver and how that affects other drugs in treatment? (I read a study where it caused a large increase in clobazam blood levels. Seventy-seven percent of patients had adverse reactions from elevated levels that was eventually relieved by lowering the clobazam dose to achieve proper drug levels. (www.ncbi.nlm.nih.gov/pubmed/26114620) Do you think people/doctors should be more aware of this effect for patients on heart/seizure and other sensitive medications?

ER: This has been extensively researched. Cannabinoids produce cytochrome P450 effects of note only at extremely high doses. In general, cannabis-based medicines produce few drug/drug interactions. Additive sedation is always possible, but seldom an issue except with the highest CBD doses. There is no drug that cannot be co-administered with cannabis. Yes, N-desmethyl clobazam levels may rise with high dose cannabidiol, but lowering clobazam dose alleviates that. Valproate is a drug that does not play well with others, and requires close monitoring in any event. (See: http://journal.frontiersin.org/article/10.3389/fphar.2016.00309/full. article download available).

CBJ: I’ve heard you discuss GPP as the starting point for terpenes and cannabinoids, are you aware of any research or work to increase GPP production?

ER: This kind of approach is not likely fruitful. Fine tuning of the endocannabinoid system is more likely to come from a healthy gut microbiome with administration of prebiotics and probiotics.

CBJ: Have you seen any work furthering the investigation of ultraviolet (UV) lighting’s connection to THC/CBD and terpene production in cannabis? John Lydon did an interesting study, but I haven’t seen any follow up.

ER: High ultraviolet exposure increases THC production, as in high elevation cultivation of cannabis in a sunny location. In the future, indoor growing will be much less desirable as prohibition necessarily falls by the wayside.

CBJ: Is there anything you think people should know about terpenes, cannabinoids, cannabis or phytochemicals that we haven’t discussed?

ER: The future of medicine must direct itself once again towards plants. Cannabis is their Queen.

Interview and introduction by David HeldrethSpecial to the Cannabiz Journal